Field of the Disclosure
Aspects of the disclosure relate to the fields of molecular biology and medicine. In particular, disclosed herein are methods for diagnosing neurological conditions in a patient using expression levels of biomarkers.
Description of the Related Technology
Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. AD is one of several disorders that cause the gradual loss of brain cells and is a leading cause of dementia. Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. Mild cognitive impairment (MCI) is often the first identified stage of AD. As the disease progresses, motor, sensory, and linguistic abilities also are affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of three to twenty years.
An early diagnosis of AD has many advantages including, for example, increased time to maximize quality of life, reduced anxiety about unknown problems, increased chances of benefiting from treatment and increased time to plan for the future. However, reliable and noninvasive methods for diagnosing AD are not available.
Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles (NFT) and beta-amyloid plaques, comprised predominantly of an aggregate of fragments known as Aβ peptides. Individuals with AD exhibit characteristic beta-amyloid deposits in the brain (beta-amyloid plaques) and in cerebral blood vessels (beta-amyloid angiopathy) as well as neurofibrillary tangles. Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-inducing disorders. On autopsy, presently the only definitive method of diagnosing AD, large numbers of these lesions are generally found in areas of the human brain important for memory and cognition.
While advances have been made in imaging beta-amyloid, (Lopresti, et al. J. Nucl. Med. (2005) 46:1959-1972), no serum biomarkers for AD are clinically available that can detect early stage AD, particularly at the stage of MCI. There are no validated biomarkers for confirming the diagnosis of a major neurodegenerative disorder or to monitor progression (Castano, et al. Neurol. Res. (2006) 28:1155-163).
Despite the enthusiasm for the use of proteomic technology to discover blood markers of AD, and decades of effort, progress towards identifying useful markers has been slow, possibly because putative high specificity AD markers are assumed to be in very low abundance because they are shed from small volumes of diseased tissue and are expected to be rapidly cleared and metabolized. In addition, researchers have avoided studying blood because the blood proteome is complicated by resident proteins such as albumin that can exist at a concentration many millions of times greater than the target low abundance biomarker. For this reason, researchers have focused on cerebrospinal fluid (CSF) as the target fluid for AD biomarkers (see Zhang et al., J. Alzheimer's Disease (2005) 8:377-3386). The CSF approach, however, has limited clinical application to routine screening. Moreover, the blood brain vascular circulation perfuses AD lesions with a higher efficiency, particularly in the case for amyloid angiopathy.